Endoplasmic Reticulum Stress Causes Liver Cancer Cells to Release Exosomal miR‐23a‐3p and Up‐regulate Programmed Death Ligand 1 Expression in Macrophages
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- Jiatao Liu
- Department of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei,China
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- Lulu Fan
- Department of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei,China
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- Hanqing Yu
- Department of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei,China
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- Ju Zhang
- Department of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei,China
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- Yong He
- Laboratory of Liver Diseases,National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health,Bethesda,MD
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- Dechun Feng
- Laboratory of Liver Diseases,National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health,Bethesda,MD
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- Fang Wang
- Department of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei,China
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- Xiaoqiu Li
- Department of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei,China
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- Qingqing Liu
- Department of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei,China
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- Yuhuan Li
- Department of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei,China
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- Zhenli Guo
- Department of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei,China
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- Bin Gao
- Laboratory of Liver Diseases,National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health,Bethesda,MD
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- Wei Wei
- Institute of Clinical Pharmacology,Anhui Medical University,Hefei,China
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- Hua Wang
- Department of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei,China
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- Guoping Sun
- Department of Oncology,The First Affiliated Hospital of Anhui Medical University,Hefei,China
説明
<jats:p>Endoplasmic reticulum (ER) stress promotes tumor cell escape from immunosurveillance. However, the underlying mechanisms remain unknown. We hypothesized that ER stress induces hepatocellular carcinoma (HCC) cells to release exosomes, which attenuate antitumor immunity by modulating the expression of programmed death ligand 1 (PD‐L1) in macrophages. In this study, we demonstrated that expression of several ER stress markers (glucose‐regulated protein 78, activating transcription factor 6, protein kinase R–like ER kinase, and inositol‐requiring enzyme 1α) was up‐regulated in HCC tissues and negatively correlated with the overall survival and clinicopathological scores in patients with HCC. Expression of ER stress–related proteins positively correlated with CD68<jats:sup>+</jats:sup> macrophage recruitment and PD‐L1 expression in HCC tissues. High‐throughput sequencing analysis identified miR‐23a‐3p as one of the most abundant microRNAs in exosomes derived from tunicamycin (TM)‐treated HCC cells (Exo‐TMs). miR‐23a‐3p levels in HCC tissues negatively correlated with overall survival. Treatment with Exo‐TMs up‐regulated the expression of PD‐L1 in macrophages <jats:italic toggle="yes">in vitro</jats:italic> and <jats:italic toggle="yes">in vivo</jats:italic>. Bioinformatics analysis suggests that miR‐23a‐3p regulates PD‐L1 expression through the phosphatase and tensin homolog (PTEN)–phosphatidylinositol 3‐kinase–protein kinase B (AKT) pathway. This notion was confirmed by <jats:italic toggle="yes">in vitro</jats:italic> transfection and coculture experiments, which revealed that miR‐23a‐3p inhibited PTEN expression and subsequently elevated phosphorylated AKT and PD‐L1 expression in macrophages. Finally, coculture of T cells with Exo‐TM–stimulated macrophages decreased CD8<jats:sup>+</jats:sup> T‐cell ratio and interleukin‐2 production but increased T‐cell apoptosis <jats:italic toggle="yes">in vitro</jats:italic>. <jats:italic toggle="yes">Conclusion</jats:italic>: ER‐stressed HCC cells release exosomes to up‐regulate PD‐L1 expression in macrophages, which subsequently inhibits T‐cell function through an exosome miR‐23a–PTEN–AKT pathway. Our findings provide insight into the mechanism how tumor cells escape from antitumor immunity.</jats:p>
収録刊行物
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- Hepatology
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Hepatology 70 (1), 241-258, 2019-04-25
Ovid Technologies (Wolters Kluwer Health)